Despite the availability of anti-tuberculosis therapy during the last five decades, the disease caused by M. tuberculosis continues to be one of the most prevalent infectious diseases worldwide. Accordingly, in 2011, nearly 9 million new cases of tuberculosis (TB) and 1.4 million deaths were reported. In addition, the World Health Organization has estimated that one third of the world population would be infected with latent M. tuberculosis (LTBI), a condition where individuals are infected by the intracellular bacteria without exhibiting active disease but with a high risk of reactivation. Primary infection leads to active tuberculosis in less than 10% of infected individuals, while in the majority of the cases the immune system is able to contain, but not eliminate, the infection, leading to LTBI. Latency can persist throughout lifetime, but weakness of the immune response of the host can lead to reactivation.
Latent tuberculosis can lead to active disease in case of immunodepression, which can be due to therapeutical treatments (for autoimmune diseases such as rheumatoid arthritis or for organ transplantation), malnutrition or old age. The situation is aggravated by the high rate of M. tuberculosis-HIV co-infection, since AIDS leads to immunosuppression and therefore to tuberculosis activation.
The existence of such a huge reservoir of the pathogen (almost 2 billion people) requires an urgent sensitive and early diagnosis of tuberculosis infection in order to control active disease. Knowing if an individual is latently infected can change treatment decision, as in the case of an organ transplant which requires an immunosupressive treatment.
Interferon gamma release assays (IGRAs) represent the most novel tuberculosis infection diagnostic assays and, despite their limitations, have been well received in most developed countries. While the M. tuberculosis antigens CFP-10 and ESAT-6 are currently being used for such diagnosis, they are not able to discriminate active and latent infection.
The lack of a gold standard for diagnosing LTBI has thus remained a main hurdle. Indeed, the identification of these subjects by sensitive and fast diagnostic tests represents a crucial aim for the eradication of tuberculosis disease and the currently available tests are not sensitive enough, being unable to differentiate between latent and active infected individuals.
The aim of this invention was thus to identify new antigens that would allow to specifically discriminate latently infected individuals from healthy controls and patients with active tuberculosis, which the currently available tests are unable to do.
A further aim was to allow a single test to discriminate among the three groups of subjects (LTBI, TB patients and healthy patients). Such test would eliminate the need of radiological and clinical data to differentiate between active and latently infected individuals.